This invention relates to novel tricyclic erythromycin derivatives. The compounds of this invention are useful as antibiotic agents in mammals, including man, as well as in fish and birds. The compounds of the present invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa. Various derivatives of erythromycin A, useful as antibiotic agents, are referred to in U.S. patent application Ser. No. 60/049,349, filed Jun. 11, 1997, and U.S. application Ser. No. 09/355092, filed Jul. 20, 1999, both of which are incorporated herein by reference in their entirety, and in U.S. patent application Ser. No. 60/063,676, entitled xe2x80x9c9-Amino-3-Keto Erythromycin Derivativesxe2x80x9d, (Yong-Jin Wu), filed Oct. 29, 1997, which is incorporated herein by reference thereto, in its entirety.
The present invention relates to compounds of the formula I 
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
R is C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, or C3-C10 cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents), said substituents being selected from the group (hereinafter also referred to as xe2x80x9cGroup Axe2x80x9d) consisting of:
(a) nitro;
(b) N3;
(c) CN;
(d) C1-C10 alkoxy;
(e) C1-C10 alkanoyl;
(f) C1-C10 alkyl;
(g) C2-C10 alkenyl;
(h) C2-C10 alkynyl;
(i) C3-C10 cycloalkyl;
(j) 4 to 10 membered heterocyclic;
(k) xe2x80x94C(O)R10;
(l) xe2x80x94C(O)OR10;
(m) xe2x80x94NR10R11;
(n) xe2x80x94NHC(O)R10;
(o) xe2x80x94NHC(O)NR10R11;
(p) xe2x80x94S(O)n, wherein n is 0,1, or 2;
(q) xe2x80x94SO2R10; and
(r) xe2x80x94SO2NR10R11;
each R1, R2, R3, and R4 is independently selected from H, C1-C12 C3-C10 alkenyl, C3-C10 alkynyl, and xe2x80x94(CR8R9)mZ, with m being an integer from 0 to 6; wherein up to two carbons of said alkyl, alkenyl, alkynyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by one or more substituents (preferably from one to four substituents), selected from Group A;
or R2 and R3, together with the carbon to which they are attached, form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N;
R5 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94Z, and xe2x80x94(CR9R10)mZ; with m being an integer from 1 to 6; wherein the alkyl, alkenyl and alkynyl can be substituted with one or more substituents (preferably from one to four substituents) selected from Group A;
R6is H, xe2x80x94C(O)O(C1-C18) alkyl or xe2x80x94C(O)(C1-C18) alkyl, wherein one or more carbons of either of said alkyl may be replaced by a heteroatom selected from O, S and N;
each R8 and R9 is independently selected from H, halo, and C1-C6 alkyl; or R8 and R9, together with the carbon to which they are attached, can form a 3 to 10 membered cyclic or heterocyclic di-radical;
each R10 and R11 is independently H, C1-C12 alkyl, aryl substituted C1-C12 alkyl, or heteroaryl substituted C1-C12 alkyl, wherein one or more carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N.
each Z is independently 4-10 membered heterocyclic or C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
T is absent or selected from the group consisting of:
(a) xe2x80x94C(O)xe2x80x94,
(b) xe2x80x94C(O)xe2x80x94Oxe2x80x94,
(c) xe2x80x94CH2xe2x80x94,
(d) xe2x80x94C(S)xe2x80x94Sxe2x80x94,
(e) xe2x80x94C(O)xe2x80x94NR10xe2x80x94;
(f) xe2x80x94S(O)nxe2x80x94, where n is 0,1, or 2,
(g) xe2x80x94S(O)nxe2x80x94Oxe2x80x94, wherein n is 0, 1, or 2,
(h) xe2x80x94P(O)(OR10)nxe2x80x94, wherein n is 0, 1, or 2, and
(i) xe2x80x94S(O)2xe2x80x94NR10xe2x80x94,
Rt is selected from the group consisting of: C1-C6 alkyl, C3-C6 alkenyl, C3-C12 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A.
The present invention also relates to compounds of formula 2: 
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
each Rw and Rx is independently H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, or C3-C10 cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substitutents) selected from Group A;
R1 is as defined for formula 1, or R1 and Rw together with the nitrogen to which they are attached can form xe2x80x94Nxe2x95x90C(R1)(R2), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R4 is as defined for formula 1, or R4 and Rx, together with the nitrogen to which they are attached, form xe2x80x94Nxe2x95x90C(R4)(R2), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R, R5, R6, Rt and T are as defined for formula 1.
The present invention also relates to compounds of formula 3: 
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
Rw is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C10 cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably 1-4 substitutents) selected from Group A;
Rz is H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C10 cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
R, R1, R5, R6, Rt and T are as defined for formula 1.
A first embodiment of the invention is a compound having the formula 1, as described above, and a preferred embodiment is a compound of formula 1 wherein R=Et, R2=R3=R4=R6=H, R5=Me, and R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 1 are those selected from the group consisting of:
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rtis (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-y, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R1=Me, R2=R3=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R4=Me, R1=R2=R3=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=Me, R1=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, TT is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R1=R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2xe2x80x94S-phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)NHxe2x80x94, Rt is allyl,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is CH(CH3)2,
Compounds of formula 1, wherein R=Et, R2=R3=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
A second embodiment of the invention is a compound having the formula 2 as described above and a preferred embodiment is a compound of formula 2 wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 2 are those selected from the group consisting of:
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 2, wherein R=Et, R1=Rw=Rx=R4=R6=H, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, xe2x80x94CH(CH3)2, or cyclohexyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 2, wherein Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 2, wherein Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CH2CH2xe2x80x94S-phenyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)NHxe2x80x94, Rt is allyl,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is CH(CH3)2,
Compounds of formula 2, wherein R=Et, Rw=Rx=R4=R6=H, R5=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
A third embodiment of the invention is a compound having the formula 3 as described above and a preferred embodiment is a compound of formula 3 wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z.
Representative compounds of the invention having formula 3 are those selected from the group consisting of:
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2, Rt is xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2S-phenyl,
Compounds of formula 3, wherein R=Et, R1=Rw=R6=H, Rz=Me, R5=xe2x80x94(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NH, Rt is (2-nitrophenyl), phenyl, allyl, CH(CH3)2, or cyclohexyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is acetyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is (4-methoxy)benzoyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, Rt is methanesulfonyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is xe2x80x94CHxe2x95x90CH2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, R1 is xe2x80x94CH2CH2N(CH3)2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94S(O)2xe2x80x94, Rt is CH2CH2xe2x80x94S-phenyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is (2-nitrophenyl),
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is phenyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is allyl,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is xe2x80x94CH(CH3)2,
Compounds of formula 3, wherein R=Et, Rw=R6=H, R5=Rz=Me, R1=xe2x80x94(CH2)3Z, Z is quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, Rt is cyclohexyl,
the pharmaceutically acceptable salts and prodrugs of the foregoing compounds.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formulas 1-3, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formulas 1-3 or a pharmaceutically acceptable salt or prodrug thereof.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
The invention also relates to a method of preparing compounds of formulas 1-3 
and pharmaceutically acceptable salts thereof, wherein R, R1-R6, Rt and T are as defined above. The compound of formula 1 is prepared as follows: treating a compound of the formula 7 
with a compound of formula R2R3C(xe2x95x90O) in the presence of an acid in a solvent. The preferred acids are formic acid, acetic acid, p-toluenesulfonic acid and the preferred solvents are THF, dichloromethane, and chloroform.
Patients that can be treated with the compounds of formulas 1-3, and/or the pharmaceutically acceptable salts and prodrugs thereof, include mammals (particularly humans), fish, and birds suffering from infections caused by various micro-organisms including Gram positive and Gram negative bacteria.
As used herein, unless otherwise indicated, the term xe2x80x9cbacterial infection(s)xe2x80x9d or xe2x80x9cprotozoa infectionsxe2x80x9d includes bacterial infections and protozoa infections which occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory diseases related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., xe2x80x9cThe Sanford Guide To Antimicrobial Therapy,xe2x80x9d 26th Edition, (Antimicrobial Therapy, Inc., 1996).
In the chemical structures depicted herein, a wavy line indicates that the stereochemistry at the chiral center to which the wavy line is connected is either an R or S configuration where the wavy line is connected to a carbon atom. In the compound of formula 3, the wavy line connected to the oxime nitrogen at position 9 of the macrolide ring indicates that the xe2x80x94ORz moiety is in an E or Z configuration.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. Said alkyl group may include one or two double or triple bonds. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
The term xe2x80x9calkanoylxe2x80x9d, as used herein, unless otherwise indicated, includes xe2x80x94C(O)-alkyl groups wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
As used herein, unless otherwise indicated, xe2x80x9cAcxe2x80x9d indicates an acetyl group.
As used herein, unless otherwise indicated, xe2x80x9cMexe2x80x9d indicates a methyl group.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 5 membered heterocyclic group is thiazolyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. In general, acceptable 4-10 membered heterocyclic groups include those derived from one of the following: furan, thiophene, 2H-pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole, 2-imidazole, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, 2H-pyran, 4H-pyran, pyridine, piperidine, 1,4-dioxane, 1,3-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, 1,3,5-triazine, 1,3,5-trithiane, indolizine, indole, isoindole, 3H-indole, indoline, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinuclidine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, tetrazole, thietane and azetidine.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I-3. The compounds of formula I-3 that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I3 that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts.
The present invention also includes all radio-labeled forms of the compounds of formula 1-3, and pharmaceutically acceptable salts thereof, wherein the radio-label is selected from 3H, 11C and 14C. Such radio-labeled compounds are useful as research or diagnostic tools.
Certain compounds of formula 1-3 may have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula 1 and mixtures thereof. In particular, the invention includes both the R and S configurations of C-2 and C-10 the macrolide ring of formula 1-3. The compounds of formula 1-3 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The preparation of the compounds of the present invention is illustrated in the following Schemes 1 to 5. 
Scheme 1 depicts the general synthesis of compound of formula 1. The synthesis of compound 4 is disclosed in U.S. provisional patent application No. 60/106,798, filed Nov. 3, 1998, which is incorporated herein in its entirety by reference thereto. Exposure of compound 4 to acidic conditions can effect the cleavage of the cladinose sugar to give the compound of formula 5. The preferred acidic condition is HCl in ethanol. The reduction of 9-hydroxyimino group of the compound of formula 5 can be effected by treating the starting compound with a reducing agent such as TiCl3 in a polar solvent such as methanol. The resulting imine of formula 6 can be converted to the corresponding amine of formula 7, by means of reduction with a reducing agent such as NaBH3CN in a polar solvent such as methanol. The conversion of the compound of formula 7 to formula 8 can be effected by following substantially the same procedures as described in PCT publication WO 9921865 (Pfizer. Inc.,Yong-Jin Wu), to wit, by treatment of the compound of formula 7 with R2R3Cxe2x95x90O in the presence of an acid catalyst such as acetic acid to PTSA (p-toluenesulfonic acid), in a solvent such as ethanol or toluene, at a temperature within the range of 40 to 80 degrees C. for a period of 1 to 24 hours. Compounds of formula 8 can be converted to that of formula 9 through alkylation or reductive alkylation by methods known to one skilled in the art. Compounds of formula 1 can be prepared from compounds of formula 9 by many methods known to those skilled in the art. 
Scheme 2 describes an alternative synthesis of the compound of formula 5. The starting compound of formula 10 is disclosed in PCT publication WO97/31929. Compounds of formula 10 can be converted to that of formula 11 by treating the compound of formula 10 with acidic conditions followed by methanol. The preferred acidic condition is HCl in ethanol. Oximation of the compound of formula 11 can be carried out by methods known to those skilled in the art. The preferred oximation condition is hydroxylamine hydrochloride and pyridine in n-butanol at 70-90xe2x96xa1C. The conversion of the compound of formula 12 to the compound of formula 5 can be effected by direct alkylation or reductive alkylation using methods known to one skilled in the art. 
Scheme 3 describes a general synthesis of compounds of formula 2. The starting compound of formula 7 is available from Scheme 1. Compound 7 can be converted to 13 through reductive alkylation or direct alkylation by a variety of methods known to those skilled in the art. Compounds of formula 2 can be synthesized from those of 13 by many methods known to one skilled in the art. 
Scheme 4 depicts the general synthesis of compound of formula 3 wherein the starting compound of formula 10 is disclosed in PCT publication WO97/31929. Compounds of formula 14 can be synthesized from the compound of formula 10 by treatment with RzONH2.HCl and base in a solvent, preferably at a temperature from 50 to 100xc2x0 C. Preferred bases include, but are not limited to, triethylamine, 2,6-lutidine, 1,8-diazabicyclo95.4.0)undec-7-ene (DBU), and N,N-diethylpropylamine. Preferred solvents include, but are not limited to, acetonitrile, methanol, ethanol, and n-butanol. The conversion of the compound of formula 14 to the compound of formula 15 can be effected through alkylation or reduction alkylation using methods known to those skilled in the art. Alternatively, compounds of formula 15 can be derived from compounds of formula 16. The synthesis of compounds of formula 16 is disclosed in U.S. provisional patent application No. 60/106,798, filed Nov. 3, 1998, which is incorporated herein in its entirety by reference thereto. Compounds of formula 15 can be synthesized from compounds of formula 16 by treatment with RzONH2.HCl and base in a solvent, preferably at a temperature from 50 to 100xc2x0 C. Preferred bases include, but are not limited to, triethylamine, 2,6-lutidine, 1,8-diazabicyclo95.4.0)undec-7-ene (DBU), and N,N-diethylpropylamine. Preferred solvents include, but are not limited to, acetonitrile, methanol, ethanol, and n-butanol. The transformation from the compounds of formula 16 to compounds of formula 3 can be achieved by many methods known to one skilled in the art. 
Scheme 5 describes the synthesis of a compound of formula 3, wherein Rw is H, R6 is H, T is xe2x80x94C(O)xe2x80x94NHxe2x80x94, as shown by the compound of formula 19. Compounds of formula 17 can be prepared from 15, wherein Rw is hydrogen. Compounds of formula 18 can be prepared by treatment the compound of formula 17 with a compound of formula Rtxe2x80x94Nxe2x95x90Cxe2x95x90O in a solvent such as toluene in the presence of a base such as 4-dimethylaminopyridine (DMAP) at 30-110xc2x0 C. The conversion of the compound of formula 18 to the compound of formula 19 can be effected by treatment with methanol at 50-70xc2x0 C.
The compounds of the present invention may have asymmetric carbon atoms. Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.
The compounds of formula 1-3 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply converting the latter back to the free base compound by treatment with an alkaline reagent and subsequently converting the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
Those compounds of the formulas I-3 which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts may be prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1-3. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The activity of the compounds of the present invention against bacterial and protozoa pathogens is demonstrated by the compound""s ability to inhibit growth of defined strains of human (Assay I) or animal (Assays II and III) pathogens.
Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds that circumvent defined mechanisms of macrolide resistance. In Assay I, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. Use of this panel enables the chemical structure/activity relationship to be determined with respect to potency, spectrum of activity, and structural elements or modifications that may be necessary to obviate resistance mechanisms. Bacterial pathogens that comprise the screening panel are shown in the table below. In many cases, both the macrolide-susceptible parent strain and the macrolide-resistant strain derived from it are available to provide a more accurate assessment of the compound""s ability to circumvent the resistance mechanism. Strains that contain the gene with the designation of ermA/ermB/ermC are resistant to macrolides, lincosamides, and streptogramin B antibiotics due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, thereby generally preventing the binding of all three structural classes. Two types of macrolide efflux have been described; msrA encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogramins while mefA/E encodes a transmembrane protein that appears to efflux only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by either a phosphorylation of the 2xe2x80x2-hydroxyl (mph) or by cleavage of the macrocyclic lactone (esterase). The strains may be characterized using conventional polymerase chain reaction (PCR) technology and/or by sequencing the resistance determinant. The use of PCR technology in this application is described in J. Sutcliffe et al., xe2x80x9cDetection Of Erythromycin-Resistant Determinants By PCRxe2x80x9d, Antimicrobial Agents and Chemotherapy, 40(11), 2562-2566 (1996). The antibacterial assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Testsxe2x80x94Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains. acr AB or acr AB-like indicates that an intrinsia multidrug efflux pump exists in the strain. Compounds are initially dissolved in dimethylsulfoxide (DMSO) as 40 mg/ml stock solutions.
Assay II is utilized to test for activity against Pasteurella multocida and Assay III is utilized to test for activity against Pasteurella haemolytica. 
This assay is based on the liquid dilution method in microliter format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth. The test compounds are prepared by solubilizing 1 mg of the compound in 125 xcexcl of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 xcexcg/ml to 0.098 xcexcg/ml by two-fold serial dilutions. The P. multocida inoculated BHI is diluted with uninoculated BHI broth to make a 104 cell suspension per 200 xcexcl. The BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37xc2x0 C. for 18 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by comparison with an uninoculated control.
This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37xc2x0 C. with shaking (200 rpm). The next morning, 300 xcexcl of the fully grown P. haemolytica preculture is inoculated into 3 ml of fresh BHI broth and is incubated at 37xc2x0 C. with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of two-fold serial dilutions are prepared. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches 0.5 McFarland standard density, about 5 xcexcl of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37xc2x0 C. Initial concentrations of the test compound range from 100-200 xcexcg/ml. The MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control.
The in vivo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in mice.
Mice are allotted to cages (10 per cage) upon their arrival, and allowed to acclimate for a minimum of 48 hours before being used. Animals are inoculated with 0.5 ml of a 3xc3x97103 CFU/ml bacterial suspension (P. multocida strain 59A006) intraperitoneally. Each experiment has at least 3 non-medicated control groups including one infected with 0.1xc3x97challenge dose and two infected with 1xc3x97challenge dose; a 10xc3x97challenge data group may also be used. Generally, all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Cornwall(copyright) syringe) is used to administer the challenge. Thirty minutes after challenging has begun, the first compound treatment is given. It may be necessary for a second person to begin compound dosing if all of the animals have not been challenged at the end of 30 minutes. The routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered into the loose skin in the back of the neck whereas oral doses are given by means of a feeding needle. In both cases, a volume of 0.2 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test. Animals are observed daily, and the number of survivors in each group is recorded. The P. multocida model monitoring continues for 96 hours (four days) post challenge.
The PD50 is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection which would be lethal in the absence of drug treatment.
The compounds of formula 1-3 and their pharmaceutically acceptable salts or prodrugs (hereinafter referred to, collectively, as xe2x80x9cthe active compounds of this inventionxe2x80x9d) may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compounds of this invention can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
To implement the methods of this invention, an effective dose of an active compound of this invention is administered to a susceptible or infected animal (including mammals, fish and birds) by parenteral (i.v., i.m. or s.c.), oral, or rectal routes, or locally as a topical application to the skin and/or mucous membranes. The route of administration will depend on the mammal, fish or bird that is being treated. The effective dose will vary with the severity of the disease, and the age, weight and condition of the animal. However, the daily dose will usually range from about 0.25 to about 150 mg/kg body weight of the patient to be treated, preferably from about 0.25 to about 25 mg/kg.
The Examples provided below illustrate specific embodiments of the invention, but the invention is not limited in scope to the Examples specifically exemplified.